Epidemiological studies indicate that humans differ markedly in their clinical responses to infection with herpes simplex viruses (HSV) type 1 or type 2. These responses vary from subclinical, to mild or severe primary, initial (non-primary first) or recurrent infections; recurrences may be very infrequent or occur as often as once every 2 weeks. Although some of this variability may be due to differences in the infecting virus type, it is more likely that it is a result of differences at the host immunogenetic level. There has been generally no clearcut correlation regarding histocompatibility genes related to cell-mediated immunity and clinical manifestations due to many infectious agents, including HSV. On the other hand, there is increasing evidence implicating immunoglobulin (Ig) allotypes and subclass Ig antibodies in the difference in responses to various infectious agents. This project brings together individuals with the epidemiological, genetic, virological, and biostatistical expertise to apply modern monoclonal antibody, purified viral protein, and Ig allotype technology to study the immunogenetics and antibody responses in several study groups comprising widely divergent subgroups. Phenotypic measurements of Ig allotypes and subclass Ig antibodies to total antigens and purified glycoproteins of HSV-1 and HSV-2 will be assayed in well-characterized sera of neonates or adults obtained from past or ongoing clinicoepidemiological projects. It will then be possible to determine any significant correlation between these immunological and genetic variables and the acquisition, clinical severity or frequency of the herpetic infection. Such information is most pertinent to prophylactic attempts by active (various types of vaccines) or passive immunization (intravenous globulin or hyperimmune globulin), or with antivirals, e.g. acyclovir, currently in use or under consideration. The detailed dissection in primary cases, and subsequent recurrences, of the development over time of antibodies in different Ig subclasses to the important viral glycoproteins will be most useful for basic and diagnostic purposes. The unique approaches to the epidemiology and genetics of antibody responses to herpes simplex viruses, as developed and applied in this project, should also provide an important model for other infectious diseases.